Estrogen Receptor (ESR1) mRNA Expression and Benefit From Tamoxifen in the Treatment and Prevention of Estrogen Receptor-Positive Breast Cancer
Estrogen Receptor (ESR1) mRNA Expression and Benefit From Tamoxifen in the Treatment and Prevention of Estrogen Receptor-Positive Breast Cancer
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DOI：
10.1200/jco.2010.32.9615
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发表时间：
2011-11-01
影响因子：
45.3
通讯作者：
Paik, Soonmyung
中科院分区：
文献类型：
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作者：
Kim, Chungyeul;Tang, Gong;Paik, Soonmyung
已经提出了几种机制来解释雌激素受体（ER）阳性肿瘤对他莫昔芬的耐药性，但尚未描述临床上有用的解释。由于内质网是他莫昔芬的治疗靶点，因此内质网表达水平与他莫昔芬的获益程度之间可能存在线性关联。然而，这种关联从未在常规的临床ER测定中得到证实，而ER目前在临床上被用作二分类标记。我们使用基因表达谱和内质网蛋白分析来帮助阐明乳腺肿瘤中他莫昔芬耐药的分子机制。患者和方法我们对来自国家乳腺和肠外科辅助项目（NSABP）试验的石蜡包埋肿瘤进行了基因表达谱分析，该试验测试了他莫昔芬作为辅助全身治疗（B-14）和预防药物（P-1）的价值。这是一个基于现有资料的回顾性子集分析。结果在B-14测试的16个基因中，ESR1是他莫昔芬获益的最强线性预测因子，包括PGR和ERBB2。基于这些数据，我们假设，在P-1试验中，他莫昔芬组中较低水平的ESR1 mRNA是两个研究组之间的主要差异。在他莫昔芬组中，只有ESR1在er阳性癌症事件中下调了2倍以上（P < 0.001）。他莫昔芬不能预防低水平ESR1表达的er阳性肿瘤。结论ESR1的低水平表达是er阳性乳腺癌耐他莫昔芬的决定因素。应该制定策略来识别、治疗和预防这类肿瘤。[J]中华医学杂志，29(4):416 -416。(C) 2011年美国临床肿瘤学会
PurposeSeveral mechanisms have been proposed to explain tamoxifen resistance of estrogen receptor (ER) -positive tumors, but a clinically useful explanation for such resistance has not been described. Because the ER is the treatment target for tamoxifen, a linear association between ER expression levels and the degree of benefit from tamoxifen might be expected. However, such an association has never been demonstrated with conventional clinical ER assays, and the ER is currently used clinically as a dichotomous marker. We used gene expression profiling and ER protein assays to help elucidate molecular mechanism(s) responsible for tamoxifen resistance in breast tumors.Patients and MethodsWe performed gene expression profiling of paraffin-embedded tumors from National Surgical Adjuvant Breast and Bowel Project (NSABP) trials that tested the worth of tamoxifen as an adjuvant systemic therapy (B-14) and as a preventive agent (P-1). This was a retrospective subset analysis based on available materials.ResultsIn B-14, ESR1 was the strongest linear predictor of tamoxifen benefit among 16 genes examined, including PGR and ERBB2. On the basis of these data, we hypothesized that, in the P-1 trial, a lower level of ESR1 mRNA in the tamoxifen arm was the main difference between the two study arms. Only ESR1 was downregulated by more than two-fold in ER-positive cancer events in the tamoxifen arm (P < .001). Tamoxifen did not prevent ER-positive tumors with low levels of ESR1 expression.ConclusionThese data suggest that low-level expression of ESR1 is a determinant of tamoxifen resistance in ER-positive breast cancer. Strategies should be developed to identify, treat, and prevent such tumors. J Clin Oncol 29:4160-4167. (C) 2011 by American Society of Clinical Oncology